Exposure to biological toxins induces the innate immune response, and is associated with many inflammatory diseases, ranging from allergy and asthma to sepsis, Crohn's disease, and atherosclerosis. Our long term goal is to identify genes and regulatory mechanisms that control the innate immune response and the pathogenesis of inflammatory immune diseases. These genes and pathways represent potential novel targets for the development of therapeutic and diagnostic options. Using a comparative genomics approach, we have identified several novel genes and a novel protein interaction network that control the production of inflammatory cytokines induced by one biological toxin, lipopolysaccharide (LPS). Several of these novel genes exhibit potentially conserved function in the regulation of innate immunity in C. elegans, murine macrophages, mice, and humans, indicating the potential importance of these conserved genes in immune regulation. However, we have not yet embarked on mechanistic studies to define how these genes function, which is a necessary prelude to establishing these genes as new therapeutic or diagnostic targets. Based on our preliminary data and the sequence of these genes, we hypothesize that the novel innate immunity genes that we have identified function either through well described innate immune signaling mechanisms that include NF?B activation or through the regulation of transport and secretion of cytokines. We therefore propose to use the exploratory R21 funding mechanism to perform mechanistic studies to clarify the function of these novel innate immune regulators. Specifically, we will determine how these novel genes regulate classical innate immune signaling pathways, including the activation of NF?B and MAP kinase signaling, and how these genes regulate cytokine transport and secretion. PUBLIC HEALTH RELEVANCE: The incidence and severity of many immunological diseases is affected both by exposure to biological toxins in the environment and by host genetic factors of the innate immune system. Common immunological diseases with an environmental component include asthma, allergy, sepsis, and Crohn's disease. The cost in mortality and financial burden on our health care system due to these diseases is staggering, including millions of lost work and school days, the loss of hundreds of thousands of lives, and the expenditure of tens of billions of dollars each year. Particularly troublesome is the fact that these diseases are growing rapidly in incidence. The goal of our proposal is to identify the key mechanisms utilized by several novel regulators of the innate immune response that we have identified. This approach will yield a new set of targets for potential prevention, diagnosis, and treatment of inflammatory diseases.